1364 DOI 10.1002/mnfr.201500955 Mol. Nutr. Food Res.

2016, 60, 1364–1373

REVIEW

Ginger augmented chemotherapy: A novel multitarget

nontoxic approach for cancer management
Roopali Saxena1 , Padmashree C. G. Rida1 , Omer Kucuk2 and Ritu Aneja1
1
Department of Biology, Georgia State University, Atlanta, GA, USA
2
Winship Cancer Institute of Emory University, Atlanta, GA, USA

Cancer, referred to as the ‘disease of civilization’, continues to haunt humanity due to its dread- Received: November 24, 2015
ful manifestations and limited success of therapeutic interventions such as chemotherapy in Revised: January 11, 2016
curing the disease. Although effective, chemotherapy has repeatedly demonstrated inadequacy Accepted: January 12, 2016
in disease management due to its debilitating side effects arising from its deleterious non-
specific effects on normal healthy cells. In addition, development of chemoresistance due to
mono-targeting often results in cessation of chemotherapy. This urgently demands develop-
ment and implementation of multitargeted alternative therapies with mild or no side effects.
One extremely promising strategy that yet remains untapped in the clinic is augmenting
chemotherapy with dietary phytochemicals or extracts. Ginger, depository of numerous bioac-
tive molecules, not only targets cancer cells but can also mitigate chemotherapy-associated
side effects. Consequently, combination therapy involving ginger extract and chemotherapeu-
tic agents may offer the advantage of being efficacious with reduced toxicity. Here we discuss
the remarkable and often overlooked potential of ginger extract to manage cancer, the possibil-
ity of developing ginger-based combinational therapies, and the major roadblocks along with
strategies to overcome them in clinical translation of such inventions. We are optimistic that
clinical implementation of such combination regimens would be a much sought after modality
in cancer management.

Keywords:
Antiemetic / Cancer / Chemotherapy / Ginger / Gingerols / Shogaols

1 Introduction ramifications on society with global spending on cancer

Cancer represents one of the deadliest and fastest growing ail-
ments worldwide with soaring morbidity and mortality. Ac-
cording to GLOBOCAN 2012, an epidemiological database
for cancer prevalence worldwide, approximately 14 million
new cases were reported in 2012 alone, along with 8.2 mil-
lion cancer-related deaths. It is projected that reported annual
new cases would rise to a staggering 22 million over the next
two decades (WHO, GLOBOCAN). Cancer not only inflicts
damage on human life but also has far-reaching economic
Correspondence: Ritu Aneja
E-mail: raneja@gsu.edu
Abbreviations: Cdks, Cyclin-dependent kinases; CINV,
Chemotherapy-induced nausea and vomiting; CPT11, Irinotecan;
6DG, 6-Dehydrogingerdione; ERK, Extracellular signal-regulated
kinases; GE, Ginger extract; 6G, [6]-Gingerol; 8G, [8]-Gingerol;
10G, [10]-Gingerol; 5-HT3 , 5-Hydroxytryptamine 3; JNK, c-Jun N-
terminal kinase; MAPK, Mitogen-activated protein kinase; NK-1,
Neurokinin-1; ROS, Reactive oxygen species; 6S, [6]-Shogaol;
4S, [4]-Shogaol
medication reaching 100 billion dollars in 2014 [1]. There-
fore, speedy increase in cancer incidence and economic
burden due to cost of cancer care present an alarming
situation for future and demand an immediate attention
to revisit conventional strategies for disease prevention
and cure.
Cancer is a heterogeneous and constantly evolving disease
with genetic and epigenetic changes occurring in the cancer
cells as well as structural and architectural changes ensuing
in the microenvironment. At the cellular level, cancer may
be defined as a mass of phenotypically and genotypically dis-
similar abnormal cells that defy the rules of conventional cell
proliferation and death pathways. In essence, cancer is a col-
lective term encompassing a conglomerate of diseases that
present with specific hallmarks. As a result, cancer cells ac-
quire a number of characteristics over time that confer them
with the ability to divide erratically and give them the ad-
vantage to invade other parts of the body. These hallmarks
include but are not limited to, sustained cell proliferation,
Colour Online: See the article online to view Figs. 1 and 2 in colour.


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Mol. Nutr. Food Res. 2016, 60, 1364–1373
avoidance of resistance to cell death, induction of angiogene-
sis, and invasion of normal healthy cells [2]. Although cancer
formation is a multifactorial phenomenon, there is enough
evidence that underlines the importance of lifestyle factors
in fueling carcinogenesis [3]. These factors include reduced
intake of fruits and vegetables, lack of exercise, stress, obe-
sity, use of tobacco etc. A combination of these factors, in
association with environmental elements, leads to chronic
inflammation and oxidative stress, primary culprits respon-
sible for the malignant transformation of cells.
Growing incidence of cancer and escalating healthcare
costs have sparked interest in the development of chemo-
preventive measures which inhibit and disrupt cancer de-
velopment and progression through long-term use of syn-
thetic, natural, or biological agents with minimal or no side
effects [4]. Owing to genotypic and phenotypic intratumor
heterogeneity, an ideal chemopreventive regimen should en-
tail targeting multiple cell survival pathways in order to
achieve utmost benefits. Dietary phytochemicals qualify as
excellent chemopreventive candidates due to their pleiotropic
and nontoxic attributes. Numerous studies highlight the
role of dietary and lifestyle factors, which can regulate pro-
inflammatory pathways and oxidative damage to cellular
macromolecules such as DNA and protein that lead to initia-
tion of tumorigenesis [5]. Dietary bioactive compounds have
also been shown to regulate the activity of enzymes such as
histone acetyl transferases and histone deacetylases respon-
sible for epigenetic changes whose accumulation over time
and other alterations in cellular homeostasis affect genome
stability that can potentially cause carcinogenesis. [6]. In ad-
dition, dietary phytochemicals have been reported to target
a variety of signaling pathways whose dysregulation is im-
plicated in cancer development such as MAPK/ERK and
PI3K/Akt/mTOR pathways [7]. Some of these bioactive com-
pounds with significance in cancer prevention and manage-
ment include gingerols, shogaols, genistein, phenylisothio-
cyanate, curcumin, resveratrol and indole-3-carbinol [6, 8].
Currently, combination therapy combining attributes of
chemotherapy, radiation and immunotherapy is considered
the most effective and prevalent approach for cancer treat-
ment. Early stage detection of cancer often results in good
survival rate, yet the effectiveness of combination therapies
in disease management is significantly limited due to their
associated side effects, which often result in discontinuation
of lengthy treatment regimens. Therefore, there is growing
interest in the development of phytonutrient-based augmen-
tation of cancer therapy that offers the advantage of being less
toxic and more economical.
2 Conventional chemotherapy: A curse in
disguise
Since the approval of the first chemotherapeutic drug in
1949, thousands of compounds have been screened as po-
tential anticancer agents. Currently, there are more than 200

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1365
chemotherapeutic agents used for cancer treatment that can
be categorized into cytotoxic drugs (anti-metabolites, alkylat-
ing agents, plant derivatives), hormones (agonists and antag-
onists) and other agents (monoclonal antibodies) [9]. These
cytotoxic agents were strategically designed to kill cells with
high proliferation rate, which was believed to be forte of can-
cer cells. As a result, these drugs target other rapidly diving
healthy cells in the body resulting in the manifestation of ad-
verse side effects of gastrointestinal, respiratory, cardiac, hep-
atic and neurological nature (Fig. 1A). Majority of currently
used chemotherapeutic agents target either DNA or various
steps of cell division/mitosis. For instance, taxanes such as
paclitaxel or docetaxel disrupt microtubules assembly which
is required for proper cell division [10], alkylating agents such
as cyclophosphamide damage DNA leading to apoptosis [11],
platinum compounds such as cisplatin interfere with cell di-
vision by crosslinking DNA strands [12] and topoisomerase
inhibitors like irinotecan target topoisomerases, which are
enzymes that regulate DNA topology during DNA replica-
tion and transcription [13]. One of the underlying causes of
adverse side effects of these chemotherapeutic agents is ac-
companying death of noncancerous healthy cells with high
proliferation rate. Cytotoxic effects of microtubule binding
agents on normal cells dwelling in interphase of cell cycle
further contribute to the toxicity of chemotherapy [14]. The
side effects of chemotherapy are classified as acute or late,
based on the time frame of their occurrence after therapy
[15]. Acute toxicity occurs within a few weeks of treatment
and affects tissues with high proliferation rate such as red
blood cells of bone marrow, gastrointestinal lining, and skin.
On the other hand, late toxicity affects patients several months
post treatment and is mainly associated with tissues with low
proliferation rate [15]. Some of the manifestations of late tox-
icity include neural and vascular damage, fibrosis, infertility,
and secondary malignancy. Chemotherapy-induced nausea
and vomiting (CINV) is the most common and debilitating
side effect of chemotherapy caused by systemic cytotoxic-
ity to gastrointestinal lining (Fig. 1B). It has been estimated
that approximately 70% of patients experience CINV despite
widespread use of antiemetic agents [16]. Chemotherapeu-
tic agents are classified into four risk groups: high, mod-
erate, low, and minimal depending on the severity of CINV
upon their administration in the absence of antiemetic agents
[17,18]. Drugs like cisplatin and streptozotocin falls under the
category of high emetic risk group while agents such as hor-
mones, gemcitabine, fluorouracil, etc. belong to low emetic
risk group. The exact mechanism of CINV has not been com-
pletely elucidated but it is suggested that chemotherapeutic
agents induce nausea and vomiting by increasing serotonin
concentration in intestine and brain stem [19]. Serotonin is
a neurotransmitter that mediates its physiological responses
via activation of serotonin receptors [20]. Serotonin medi-
ated activation of vomiting center and/or chemoreceptor trig-
ger zone located in brain, via central and peripheral neural
processes, has been proposed to be predominantly respon-
sible for CINV (Fig. 1B). 5-hydroxytryptamine receptors-3
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1366 R. Saxena et al. Mol. Nutr. Food Res. 2016, 60, 1364–1373

Figure 1. (A) Side effects of chemotherapy. Chemotherapy is one of the most prevalent interventions to treat cancer but its application
causes various adverse side effects in patients as depicted in the figure. These side effects can be gastrointestinal, cardiac, respiratory,
hepatic, or neurological and their extent and severity vary by person and therapeutic agent. (B) Chemotherapy-induced nausea and
vomiting. CINV is the most prevailing side effects of chemotherapy. CINV is induced by stimulation of vomiting center and/or chemoreceptor
trigger zone located in brain through serotonin-activated neural pathways. Although patients are prescribed antiemetic agents to alleviate
CINV, benefits of such agents are limited due to their associated toxicity.

(5-HT3 ) are known to particularly mediate acute nausea and
vomiting while activation of neurokinin-1 receptors (NK-1)
by substance P is associated with delayed responses [15].
Agents that block these receptors, termed antiemetic recep-
tor antagonists, are normally prescribed to patients under-
going chemotherapy in order to limit CINV [21]. Commonly
prescribed antiemetic agents include dopamine receptor an-
tagonists such as haloperidol and metoclopramide, 5-HT3
receptor antagonists such as ondansetron, granistron, and
dolasetron and NK-1 antagonist aprepitant [22]. Although ef-
fective, some of these emetic agents can themselves cause
side effects, which limit their use in clinical practice. For in-
stance, use of haloperidol can lead to dystonia and sedation
in treated patients [22]. In addition to CINV, acute diarrhea
is another well-known and common gastrointestinal side ef-
fect particularly associated with the use of chemotherapeutic
agents such as 5-fluorouracil and irinotecan (CPT11). The
toxicity of CPT11 is due to its metabolic transformation into a
toxic metabolite called SN38, which can cause mucosal dam-
age leading to exudative processes along with malabsorption
of water and electrolytes [23, 24].
While gastrointestinal side effects constitute the most
prevalent and widely recognized side effects, chemother-
apy induces a wide array of other systemic perturbations of
cardiovascular, respiratory, hepatic, renal, and neurological
nature that are associated with specific chemotherapeu-
tic agents [9]. For instance, cardiovascular complications
are more commonly associated with the use of anthra-
cyclines, 5-fluororacil, and cyclophosphamide and include
cardiomyopathy and heart failure due to myocyte death and fi-
brosis, arrhythmias, coronary ischemia, and vascular inflam-
mation [9, 25]. Although generation of free radicals and con-
sequent cellular damage are key mechanistic players in the
development of cardiotoxicity, other proposed mechanisms
include modulation of intracellular ATP production and car-
diac topoisomerase enzyme activity [25]. Patients undergo-
ing chemotherapy generally develop secondary respiratory
infections due to immunosuppressive effects of chemother-
apy [9]. Hepatic impairment constitutes an uncommon and
unpredictable side effect of systemic chemotherapy and may
lead to manifestations from jaundice to acute hepatic fail-
ure. Chemotherapy mediates renal disease and electrolyte
disturbances by its effects on glomerulus, tubules, intersti-
tium, or the renal microvasculature leading to delayed re-
nal clearance of chemotherapeutic agents and their active
metabolites [9]. Further, chemotherapy can cause injuries to
central and peripheral nervous system leading to the devel-
opment of sensory and motor neuropathies, transient asep-
tic meningitis, transverse myelitis, seizures, and permanent
leucoencephalopathy [9]. Other notable adverse neurotoxic


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Mol. Nutr. Food Res. 2016, 60, 1364–1373
conditions include mood changes and neurocognitive alter-
ations such as memory loss, impaired attention, and decline
in concentration and processing speed which are mediated
by plausible effects of chemotherapy on hippocampal func-
tion [26]. Although neurological side effects are observed
across the whole spectrum of cytotoxic agents, the exact
mechanism underlying these effects remains elusive owing
to the use of multiple agents during combination therapy [26].
Chemotherapy-induced neurotoxicity represents a relatively
new field of investigation in clinical oncology and neurotox-
icity management is generally overlooked in patients due to
lack of validated tests and standardized guidelines for the
assessment of neurological symptoms including cognitive
dysfunction. Although neuroimaging techniques provide a
detailed analysis of cognitive function by assessing the struc-
tural and functional effects of chemotherapeutic agents on
brain, studies should be aimed at designing and validating
simple neurological tests for accurate and quick assessment
of cognitive dysfunction in cancer patients [27]. Despite ex-
tensive research focused on understanding and combating
chemotherapy-induced side effects, detailed molecular mech-
anisms underlying chemotherapy-induced side effects are not
completely known and for some of them, no treatment yet
exists.
3 Ginger: A rooty panacea
Indigenous to Southeast Asia, ginger is valued for its un-
matched medicinal properties since ancient time and has
spread worldwide by means of spice trade. Ginger is referred
to as the universal remedy and constitutes an integral part
of traditional Chinese and Indian Ayurvedic medicine. The
underground stem of ginger plant, called as rhizome, has
been traditionally known to treat a range of gastrointestinal
disorders such as constipation, dyspepsia, gastritis, indiges-
tion, nausea, and vomiting along with other ailments includ-
ing arthritis, rheumatism, sprains, muscle aches, sore throat,
cramps, hypertension, dementia, fever, gingivitis, asthma,
stroke, and diabetes [8]. The phytochemical composition of
ginger rhizome is diverse containing both volatile and non-
volatile molecules, responsible for its flavor and aroma, along
with a proteolytic enzyme called zingibin and the relative
abundances of ginger constituents depend on various ge-
ographical, environmental, and agricultural factors [28, 29].
The volatile component of ginger is mainly constituted of
mono- and sesquiterpenes with zingiberol being the prin-
cipal aroma-contributing molecule. The nonvolatile compo-
nents are responsible for pungency of ginger and consist
mainly of gingerols, shogaols, paradols, and zingerone [30].
These compounds are biologically active and account for most
of the pharmacological effects of ginger [28]. Gingerols con-
stitute a series of chemical homologs that differ from each
other in alkyl chain length and a side chain, with 6-gingerol
being the most abundant one. Gingerols are sensitive to heat
and can easily undergo dehydration to form shogaols. This

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1367
results in enrichment of shogaols in dried or thermally treated
ginger as opposed to fresh ginger that has large quantities of
gingerols [31].
Since ginger harbors numerous bioactive molecules with
diverse pharmacological properties, it can be appropriately
referred to as ‘natural panacea’ and can be employed to treat
a variety of ailments. Given the diverse composition of gin-
ger, its beneficial effects in various pathological conditions
are by virtue of targeting an array of signaling pathways.
Ginger and its constituents can prevent the buildup of ox-
idative stress that can damage cellular macromolecules un-
derlying various pathological conditions [32]. This is achieved
in a variety of ways such as scavenging free radicals, modu-
lating levels of antioxidant molecules (glutathione) and en-
zymes (superoxide dismutase, catalase), and modulating lev-
els of phase I (cytochrome P450) and phase II (glutathione
S-transferase) drug metabolizing enzymes [33]. Many gin-
ger constituents possess anti-inflammatory properties and
exert their effects by suppression of prostaglandin and
leukotriene synthesis and pro-inflammatory cytokines such
as interleukin-1, tumor necrosis factor-␣, and interleukin-8
[33–35]. Ginger acts as a dual inhibitor of enzymes such as
cyclooxygenase 1 and 2 (COX 1 and 2) and 5-lipoxygenase (5-
LO) which are involved in the biosynthesis of inflammation
mediators such as prostaglandins and leukotrienes [36, 37].
As a result, extended use and high doses of ginger do not
cause toxicity often associated with the use of NSAIDs which
shifts arachidonic metabolism toward increased synthesis
of pro-inflammatory leukotrienes [35, 38]. The broad effect
of ginger on inflammation can be attributed to its ability
to regulate expression of NF-␬B, a master regulator of pro-
inflammatory genes coding for chemokines and cytokines
[35, 39]. For instance, it has been shown that ginger extract
inhibits expression of NF-␬B in activated synoviocytes [40].
The anti-microbial properties of ginger are mediated through
anti-bacterial and anti-fungal effects of gingerols as well as
other bioactive constituents such as paradols, zingerone, and
shogaols [34]. Further, ginger constituents are reported to
modulate ‘tumor-permissive’ signaling pathways, which con-
tribute to the antitumor property of ginger. For example,
[6]-gingerol (6G) has been shown to block p38 MAP kinase-
NF-␬B signaling pathway by suppressing the expression of
cyclooxygenase-2 [41, 42] while [6]-shogoal (6S) inhibited NF-
␬B activation by preventing dimerization of Toll-like receptors
4, attesting to pleiotropic nature of ginger constituents [43].
4 Ginger in the war against cancer:
Where do we stand today?
The anticancer property of ginger needs no introduction
and is predominantly mediated by its constituents such as
gingerols, shogaols, and paradols. Numerous studies con-
ducted in the last two decades have demonstrated that ginger
extract (GE) and its constituents exhibit antitumor activity
against a variety of cancer cell lines and tumor xenografts by
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1368 R. Saxena et al.
employing multiple mechanisms [33]. 6G has been shown to
inhibit cell proliferation and induce apoptosis in human col-
orectal cancer cells through downregulation of cyclin D1 and
upregulation of pro-apoptotic cytokine called nonsteroidal
anti-inflammatory drug (NSAID)-activated gene-1 [44]. On
the other hand, [10]-gingerol’s (10G) anticancer properties
against human colorectal cancer cells stem from its ability to
induce slow and sustained release of calcium ions from en-
doplasmic reticulum in a concentration-dependent manner
[45]. Further, 6S was demonstrated to induce cell death in col-
orectal cancer cells by mechanisms involving modulation of
mitochondrial function though generation of reactive oxygen
species (ROS) leading to cytochrome c release [46]. Several
other studies have confirmed that 6G and 6S induce caspase-
dependent apoptosis in colon and prostate cancer cell lines
through their effects on ERK1/2/JNK/AP-1, STAT3, and NF-
␬B signaling pathways [47, 48]. In another study, a cysteine-
conjugated metabolite of 6S (M2) was found to be as effective
as 6S in inducing apoptotic pathway leading to reduction in
cancer cell proliferation and tumor regression in mouse mod-
els but with reduced toxicity against normal cells than 6S [49].
Another constituent of ginger, 6-dehydrogingerdione (6DG)
has been observed to trigger mitochondrial apoptotic path-
way in breast cancer cells via mechanisms involving ROS
and c-Jun N-terminal kinase [50]. Further, 6DG has been
demonstrated to mediate its anti-inflammatory effects by at-
tenuating enzymes nitric oxide synthase and cyclooxygenase-
2 and pro-inflammatory cytokines such as interleukin-1␤,
interleukin-6, and tumor necrosis factor-␣ [51]. Ginger phy-
tochemicals not only inhibit proliferation of cancer cells but
can also potentially prevent cancer metastasis by preventing
invasion of healthy normal cells by cancer cells. To this ef-
fect, [4]-shogaol (4S) has been shown to cause mesenchymal-
epithelial transition therefore reducing metastasis in breast
cancer in animal models [52]. Further, [6]-shogaol has been
reported to inhibit cancer cell invasion by downregulating
matrix metalloproteinase-9 in MDA-MB-231 cells [53]. Since
different constituents of ginger exert their effects by targeting
multiple and diverse pathways, studies conducted with GE,
rather than individual components, offer advantage of ex-
ploiting anti-cancer synergy between different components.
It has been demonstrated that the combination of ginger phy-
tochemicals with GE is more effective in inhibiting growth of
prostate cancer cells in comparison to isolated phytochemi-
cals or GE alone [54]. In a related study, GE was found to be
more effective in inhibiting prostate tumor growth in nude
mice than an artificially formulated mix that consisted of the
most abundant components of GE (6G, 8G, 10G, and 6S)
[55]. While these synergistic interactions have been amply
demonstrated, most of the molecular details pertaining to
their mechanistic interplay are yet to be determined. In one
study based in Japan, researchers tested the efficacy of (GE)
against pancreatic cancer cell lines. The study demonstrated
that treatment of pancreatic cancer cells with ginger extract
resulted in inhibition of cell cycle progression with conse-
quent induction of ROS-mediated cell death called autosis

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Mol. Nutr. Food Res. 2016, 60, 1364–1373
[56]. Although further studies are warranted, we extrapolated
mice efficacy data to humans by performing allometric scal-
ing calculations, and the human equivalent effective dose
of GE for reduction of tumor burden was found to be 567
mg for a 70 kg adult [57]. Reports from randomized human
clinical trials have revealed that daily consumption of a dose
of up to 5 grams of ginger extract (dry form) are nontoxic
with the exception of mild stomach upset in individuals who
do not normally consume spicy foods while higher doses
(6 grams or more) resulted in gastric irritation with loss of
protective intestinal mucosa [54]. In addition to possessing
anticancer properties, ginger constituents are also promising
candidates for chemopreventive interventions. In this regard,
topical application of GE has been reported to significantly
reduce 12-0-tetradecanoylphorbol-13-acetate induced hyper-
plasia and tumor incidence in SENCAR mouse [58]. Simi-
larly, zerumbone, a ginger sesquiterpene, has been shown
to inhibit 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
induced lung tumorigenesis in A/J mouse [59].
Although a body of literature supports the preventive and
therapeutic antitumor roles of ginger and its constituents,
there is still a long way to go before ginger can be imple-
mented in cancer therapy in humans. There are a num-
ber of factors that limit the potential use of ginger to treat
cancer but the most significant ones include poor bioavail-
ability of ginger constituents, lack of standard GE for treat-
ment owing to variation in its composition by various factors,
and poor understanding of pharmacokinetic properties and
metabolic transformations of ginger constituents alone and
in combination with other components. Further, the max-
imum levels of 6G achievable in the plasma reported by
pharmacokinetic studies are much lower than the reported
in vitro effective half-maximal dose thus limiting its poten-
tial efficacy in humans [57]. Oral bioavailability of various
ginger constituents can vary and depends on multiple fac-
tors such as solubility and stability in gastrointestinal fluid,
membrane permeability, transporter-driven intestinal efflux,
presystemic gut wall metabolism, and presystemic hepatic
metabolism [60]. Research aimed at devising strategies to
increase bioavailability of ginger constituents would aid in
including ginger in chemotherapeutic regimens. As men-
tioned earlier, composition of GE depends on various fac-
tors some of which are not under the control of researchers
such as geographical and environmental factors. Since phar-
macological effects of ginger depend on its composition,
the use of nonstandardized extract, and lack of pharmacoki-
netic signature of GE associated with pharmacological ef-
fects in different studies limit the use of these results in
designing and implementing ginger-based regimens for can-
cer treatment. In view of these facts, it is vital to first es-
tablish the most effective and standard composition of GE
for its anticancer effects to increase the reliability and repro-
ducibility of various studies conducted with it. In addition to
this, studies aimed at understanding pharmacokinetic prop-
erties and metabolic transformation of ginger constituents
alone and in combination with other constituents are
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Mol. Nutr. Food Res. 2016, 60, 1364–1373
warranted to better understand the synergy between different
components.
5 Combining ginger and chemotherapy:
Taming of the shrew
Chemotherapy is one of the most prevalent interventions
to treat cancer but it inflicts severe distress to patients ow-
ing to its adverse side effects, which limit its full utiliza-
tion in treating cancer. Therefore, there is a pressing need
for the development and implementation of alternative ther-
apies with mild or no side effects. One strategy that has
tremendous potential is combining chemotherapy with di-
etary agents such as ginger. This combinatorial approach
provides twofold advantage over conventional therapies in
practice (Fig. 2). First, antiemetic, antioxidant, and anti-
inflammatory attributes of ginger can be exploited to alleviate
chemotherapy-induced side effects. Second, ginger and its
constituents possess anticancer properties, which can work
in synergy with chemotherapy making the combination ther-
apy more effective than chemotherapy alone. Here, we em-
phasize on the possibility of using ginger in combination
with chemotherapy with the hope of increasing the effective-
ness of chemotherapy along with ameliorating its side ef-
fects. The effectiveness of this combination therapy relies on
antiemetic, antioxidant, and anticancer properties of ginger.
The antiemetic attributes of bioactive constituents of ginger

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1369
Figure 2. Benefits of combining gin-
ger with chemotherapeutic regimens in
practice. Various bioactive molecules
present in ginger (shown in fig-
ure) are responsible for its anti-
cancer, antiemetic, antioxidant, and
anti-inflammatory effects. These phys-
iologically important attributes of
ginger can be exploited to allevi-
ate chemotherapy-induced side ef-
fects and to make therapy more ef-
ficacious when used in combination
with chemotherapeutic regimens in
practice.
can reduce chemotherapy generated gastrointestinal symp-
toms such as vomiting and nausea. This would further help in
reducing electrolyte imbalances and severe dehydration and
in regaining lost appetite caused by chemotherapy-induced
vomiting and nausea. In addition, treatment with chemother-
apeutic agents can cause oxidative injury to normal healthy
cells, which can be ameliorated by antioxidant properties of
various ginger constituents. For instance, 6G has been shown
to provide cardioprotection against doxorubicin-induced car-
diotoxicity through its antioxidant effects and modulation
of NF-␬B signaling pathway in rat models [61]. It has been
proposed that ginger phytochemicals (6G, 8G, 10G and 6S)
function as 5-HT3 and NK-1 antagonists [62]. As mentioned
previously, antagonism of 5-HT3 and NK-1 receptors lead to
antiemetic effects by stalling stimulation of vomiting cen-
ter. Therefore, use of ginger would be as effective as 5-HT3
and NK-1 receptors antagonists in alleviating chemotherapy-
induced nausea and vomiting but without the side effects.
Furthermore, anti-inflammatory effects of ginger have been
shown to reduce cell injury in the gastrointestinal tract, which
promotes localized tissue damage through the release of
pro-inflammatory factors [63]. In addition, since ginger con-
stituents target many signaling pathways to inhibit growth
of cancer of cells, use of ginger in combination with other
chemotherapeutic agents may result in synergism of their an-
ticancer effects making combination therapy more effective
than chemotherapy alone. This could possibly reduce the rec-
ommended dose of treatment that would further reduce side
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1370 R. Saxena et al.
effects. Therefore, the twofold advantage is that ginger can
be used to prevent/treat cancer development through its ef-
fects on oxidative stress and inflammation (two major tumor
initiators and promoters) while subduing the most prevalent
side effects of chemotherapy such as vomiting and diarrhea,
which often result in discontinuation of the treatment [64].
Although there exists no clinical trial that verified the
efficacy of ginger in treating cancer in humans, there has
been one clinical trial that investigated the role of gin-
ger extract in chemoprevention of colorectal cancer [65].
In this pilot study, 21 subjects with high risk for colorec-
tal cancer were assigned to placebo or ginger group, ad-
ministered with 2.0 g ginger daily for 28 days and base-
line and 28-day levels of prostaglandin E2, leukotriene B4,
13-hydroxy-octadecadienoic acids, and 5-, 12-, & 15-hydroxy-
eicosatetraenoic acid were quantified in the colonic mucosa
of the subjects. The study reported that ginger was not effec-
tive in decreasing eicosanoid levels in subjects at high risk
for colorectal cancer [65]. However, it should be noted that
the study was a pilot study associated with limitations such
as small sample size and large subject-to-subject variation in
eicosanoid levels. Therefore, detailed and more systematic
clinical trials are warranted to completely explore the chemo-
preventive and chemotherapeutic roles of ginger. The focus
of most ginger-based clinical trials has been toward testing
the effectiveness of ginger in ameliorating chemotherapy-
induced side effects but no consensus has been achieved on
this due to a variety of caveats associated with these stud-
ies. For instance, a randomized, double-blind and placebo-
controlled clinical trial was conducted with 576 patients to as-
sess the effectiveness of ginger in ameliorating acute CIN in
cancer patients receiving 5-HT3 receptor antagonist antiemet-
ics [66]. Patients were randomly assigned to one of four
groups: placebo, 0.5, 1.0, or 1.5 g of ginger and were ad-
ministered their assigned dosage of ginger or placebo twice
daily for a total of 6 days starting 3 days before the first day
of chemotherapy. Severity of nausea was evaluated based on
a 7-point rating scale (“1” = “Not at all Nauseated” and “7” =
“Extremely Nauseated”) as reported by patients for days 1–4
of each cycle. Results of the study showed that daily admin-
istration of 0.5 and 1.0 g ginger was most effective in reduc-
ing acute chemotherapy-induced nausea. While the major
strengths of the study include large sample size and double-
blinded treatment to eliminate bias in result evaluation, the
major caveat of the study was not controlling for chemother-
apy regimens (i.e., high versus low emetogenic regimens)
[66]. Similar beneficial effects of ginger in reducing the preva-
lence of acute nausea was reported in the study conducted by
Panahi et al. wherein women with advanced stage breast can-
cer received daily dose of 1.5 g of ginger in addition to stan-
dard antiemetic therapy [67]. Further, a study conducted by
Pillai et al. confirmed the ability of ginger to reduce acute and
delayed CINV in children and young adults receiving high
emetogenic chemotherapy [68]. In addition to this, there have
been some contradicting reports that do not support benefits
of ginger to treat chemotherapy-associated side effects. Study

C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Mol. Nutr. Food Res. 2016, 60, 1364–1373
conducted by Zick et al. reported that ginger provides no ad-
ditional benefit to reduce the severity or prevalence of CINV
when given with antiemetic agents [69]. Although majority of
studies confirm the effectiveness of ginger in reducing CINV,
clinical applicability of these studies is limited due to caveats
associated with them and the existence of conflicting reports.
6 Future of ginger-augmented
chemotherapy: It is looking good
With the identification of the role of dietary and lifestyle
factors in cancer pathogenesis, disease prevention and
treatment should be directed toward combining beneficial
dietary agents obtained from fruits and vegetables. The phyto-
chemicals found in fruits and vegetables include carotenoids,
polyphenolics, anthocyanins, terpenes, and alkaloids which
have been reported to target signaling cascades which are
specifically altered in cancer cells [70]. Specifically, these phy-
tochemicals are known to prevent DNA damage, reduce ox-
idative stress, and regulate inflammatory processes thereby
reducing the overall risk of cancer development and progres-
sion [70]. With recent reports suggesting that only less than
15% of US adults consume enough fruits and vegetables to
meet their daily recommendations, it is essential to exploit
other sources of dietary phenolics for cancer prevention and
treatment. Ginger qualifies as an excellent candidate to be ap-
plied for such interventions and can be used in various ways.
Presence of numerous anticancer agents in ginger points
out that ginger alone can be potentially used to treat can-
cer. However, due to long treatment time associated with any
natural therapy, less aggressive and early stage cancers with
long latency are most likely to be benefitted from such ther-
apy. In such a scenario, combining ginger with other dietary
phenolics and a chemotherapeutic agent would yield more
beneficial results against aggressive and advanced stage can-
cers. Several dietary agents including grape seed proantho-
cyanidins, green tea polyphenols, silymarin, genistein, and
curcumin affect cell cycle progression and induce apoptosis
in various cancer cells [71]. Clinical studies should be aimed
at combining several dietary agents to increase their potency
and effectiveness since single agent intervention often fails
in disease management due to the development of resistance
with their extended use [72]. To this effect, Rhazya stricta in
combination with GE was found to synergistically suppress
proliferation and induce apoptosis in human glioblastoma
cells [73]. This study is an example of how these phytochem-
icals can be synergistically employed to simultaneously tar-
get several characteristic signaling pathways of cancer cells.
Further, studies aimed at understanding the mechanisms re-
sponsible for synergy between ginger and other phytochem-
icals and chemotherapeutic agents would provide a neces-
sary framework for the development of ginger-based cancer
interventions.
Potential use of ginger in cancer therapy first demands val-
idation of its anticancer effects in humans. However, use of
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Mol. Nutr. Food Res. 2016, 60, 1364–1373
nonstandard GE in studies related to its anticancer properties
and lack of knowledge of pharmacokinetic and pharmacody-
namic relationship for its constituents represent major obsta-
cles in clinical translation of these studies. Pharmacological
effects of ginger depend on its constituents such as gingerols,
shogaols, and paradols whose concentrations in ginger de-
pends on many factors. In addition, compositional variations
in different GE preparations can arise from different harvest
times and methods of harvest, storage, and extraction. The
foremost step toward practical application of ginger in cancer
therapy is to identify the most effective ginger composition as
a standard extract which can be universally used for ginger-
based studies. One potential strategy to standardize extract
preparations is to establish a compositional fingerprint cor-
responding to most efficacious composition of ginger. This
fingerprint can serve as gold standard for extract preparations
for ginger-based studies worldwide. Results obtained from
these studies would be much more reliable and can be conve-
niently compared with each other to draw holistic inferences
on biological effects of ginger. The use of alternative therapies
has gained popularity in the recent years with dependence on
chemopreventive and chemotherapeutic dietary agents to re-
duce toxicity and resistance encountered with current clinical
drugs [4, 72]. The future of milder and more effective cancer
therapy relies on studies and clinical trials conducted with
systematic and regimented combinations of dietary pheno-
lics alone and in combination with chemotherapeutic agents
in practice. The low-cost and down-to-earth strategy of incor-
porating the ginger rhizome and other dietary phenolics in
routine cancer therapy could thus potentially make a substan-
tial difference to cancer patients’ outcomes and mitigate the
toll that chemotherapy takes, naturally.
The authors would like to acknowledge Angela Ogden for her
input in designing the figures.
The authors have declared no conflict of interest.
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